Humble Stephen R
Department of Anaesthetics and Pain Management, Charing Cross Hospital, Imperial College NHS Healthcare Trust London, London, W6 8RF, UK.
Imperial College London, Charing Cross Campus, Margravine Road, London, W6 8RP, UK.
F1000Res. 2017 Apr 18;6:506. doi: 10.12688/f1000research.11056.2. eCollection 2017.
Recent work in a model of diabetic neuropathy revealed that layer 2/3 cortical pyramidal neurones of the pain pathway exhibited reduced endogenous neurosteroid modulation of the GABA R and exogenously applied neurosteroids had an exaggerated impact. It is postulated that this is related to reduced precursor synthesis, due to mitochondrial dysfunction in diabetic neuropathy. Benzodiazepines are also known to activate neurosteroidogenesis by binding to mitochondrial translocator protein (TSPO). This study explored the differential effect of diazepam on GABA R modulation via neurosteroidogenesis in diabetic and wild type (WT) mice. Whole-cell patch-clamp technique was used on slices of neural tissue. Electrophysiological recordings were obtained from layer 2/3 cortical pyramidal neurons of the pain pathway from mice with type-II diabetic neuropathy ( ) and WT controls aged 60-80 days. There was a key difference in the response of the WT and cortical neurons to simultaneous incubation with diazepam and flumazenil. In contrast, diazepam and the 5a-reductase inhibitor finasteride, individually or in combination, produced the same response in both strains. The exaggerated effect of diazepam on GABAergic inhibitory tone in the , despite the presence of the GABA R benzodiazepine antagonist flumazenil is likely observed due to physiological upregulation of key neurosteroidogenic enzymes in response to the reduced pregnenolone synthesis by the mitochondria. By increasing pregnenolone via TSPO activation, it is possible to promote enhanced neurosteroidogenesis and increase GABAergic inhibitory tone via an alternate route. In diabetic neuropathy, mitochondrial dysfunction may play an important role. Enhancing the GABAergic neurosteroid tone could be of potential therapeutic benefit.
近期在糖尿病性神经病变模型中的研究表明，疼痛通路的第2/3层皮质锥体神经元对GABA受体的内源性神经甾体调节作用减弱，而外源性应用神经甾体则产生了夸大的影响。据推测，这与糖尿病性神经病变中线粒体功能障碍导致前体合成减少有关。苯二氮䓬类药物也已知可通过与线粒体转位蛋白（TSPO）结合来激活神经甾体生成。本研究探讨了地西泮通过神经甾体生成对糖尿病小鼠和野生型（WT）小鼠GABA受体调节的差异作用。在神经组织切片上使用全细胞膜片钳技术。从60 - 80日龄的II型糖尿病性神经病变小鼠（ ）和WT对照小鼠的疼痛通路第2/3层皮质锥体神经元获取电生理记录。WT和 皮质神经元对同时与地西泮和氟马西尼孵育的反应存在关键差异。相比之下，地西泮和5α - 还原酶抑制剂非那雄胺单独或联合使用时，在两种品系中产生相同的反应。尽管存在GABA受体苯二氮䓬拮抗剂氟马西尼，但地西泮对 中GABA能抑制性张力的夸大作用可能是由于关键神经甾体生成酶的生理上调，以应对线粒体孕烯醇酮合成减少。通过TSPO激活增加孕烯醇酮，有可能促进增强的神经甾体生成，并通过另一条途径增加GABA能抑制性张力。在糖尿病性神经病变中，线粒体功能障碍可能起重要作用。增强GABA能神经甾体张力可能具有潜在的治疗益处。
